Avermectin compounds are 16-membered macrocyclic lactones that are potent anthelmintic and antiparasitic agents against a wide range of internal and external parasites. The compounds which belong to this series are either natural products or are semi-synthetic derivatives thereof. The natural product avermectins are disclosed in U.S. Pat. No. 4,310,519 to Albers-Schonberg, et al., and the 22, 23-dihydro avermectin compounds are disclosed in Chabala, et al., U.S. Pat. No. 4,199,569. For a general discussion of avermectins, which include a discussion of their uses in humans and animals, see “Ivermectin and Abamectin,” W. C. Campbell, ed., Springer-Verlag, New York (1989). Furthermore, bioactive agents such as avermectins or ivermectin can be used in combination with other bioactive agents; and, with respect to avermectins, ivermectin, and bioactive agent combinations, reference is made to Kitano, U.S. Pat. No. 4,468,390, Beuvry et al., U.S. Pat. No. 5,824,653, von Bittera et al., U.S. Pat. No. 4,283,400, European Patent Application 0 007 812 A1, published Jun. 2, 1980, U.K. Patent Specification 1 390 336, published Apr. 9, 1975, European Patent Application 0002 916 A2, Ancare New Zealand Patent No. 237 086, Bayer New Zealand Patent 176193, published Nov. 19, 1975, inter alia. These prior publications and all other publications cited herein are expressly incorporated by reference.
A number of antiparasitic and anthelmintic products on the market contain ivermectin as an active ingredient. For example, IVOMEC Premix manufactured and sold by Merial is a free-flowing meal mixture containing 0.6% ivermectin for incorporation into animal feeding stuffs. It is indicated as an anthelmintic, insecticide and miticide against parasites in pigs and horses (the trade name in horses is Zimecterin EZ). IVOMEC Premix offers unsurpassed efficacy against mange mites, lice and gastrointestinal worms of pigs. Mixed into the feed it may be used in all classes of pigs and makes all round parasite control convenient and easy to apply. This compound treats a variety of parasites including gastro-intestinal worms such as Ascaris suum, Hyostrongylus rubidus, Oesophagostomum spp., Strongyloides ransomi, Lungworms such as Metastrongylus spp., Lice such as Haematopinus suis, Mange mites such as Sarcoptes scabiei var. suis. Ivomec premix for pigs given to pregnant sows before farrowing effectively controls transmission via the milk of S. ransomi to piglets. Avermectins are susceptible to both acid and base catalyzed decomposition. For example, the stability testing of Ivomec Swine Premix indicated that the shelf life of the drug decreases over time, possibly due to increase of ivermectin degradate resulted from acid/base catalyzed decomposition.
Some studies have shown that by incorporating stabilizers into the medicated feed of some animals, said stabilizers can prevent or decrease the degradation of the active ingredient and increase the shelf life of such compounds. For example, U.S. Pat. No. 5,891,491 to Owens et al. have used substituted 1,2-dihydroquinoline compound, in the feed of animals in an amount sufficient to increase the shelf life of the feed. Also, U.S. Pat. No. 4,597,969 to Maxfield et al. have disclosed a method of granulation involving polysaccharide gelling agents and metal salts for the stabilization of heat and or moisture sensitive drugs or food supplement such as efrotomycin, avermectins, milbemycins, moxidectin, and other drugs.
In light of the above, it is an object of the present invention to provide for a stabilized premix comprising at least one avermectin or milbemycin derivative for feed or feed-like formulations that exhibit improved shelf life by decreasing or preventing the formation of the degradates of the active ingredient. Moreover, it is an object of the invention to provide for a method of decreasing or preventing the formulation of degradates in a premix comprising at 1 least one a vermectin or milbemycin derivative. These and other objects will become apparent from the following Description of the Invention.